Differential effect of lactate on synovial fibroblast and macrophage effector functions

Frontiers in Immunology

Immunology

Ghada Alsaleh¹  Meriam Nefla²  Sally A. Clayton²  Jennifer Marshall²  Andy R. Clark²  Andrew Filer²  Vincent Gauthier³  Valentina Pucino³  Christopher D. Buckley³  Karim Raza⁴ 

[1] Kennedy Institute of Rheumatology, Oxford University, Oxford, United Kingdom;Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom;Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom;Kennedy Institute of Rheumatology, Oxford University, Oxford, United Kingdom;Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom;Sandwell and West Birmingham National Health System (NHS) Trust, Birmingham, United Kingdom;

关键词: lactate;    fibroblasts;    macrophages;    arthritis;    cell metabolism;   

DOI  :  10.3389/fimmu.2023.1183825

 received in 2023-03-10, accepted in 2023-05-05,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionThe synovial membrane is the main site of inflammation in rheumatoid arthritis (RA). Here several subsets of fibroblasts and macrophages, with distinct effector functions, have been recently identified. The RA synovium is hypoxic and acidic, with increased levels of lactate as a result of inflammation. We investigated how lactate regulates fibroblast and macrophage movement, IL-6 secretion and metabolism via specific lactate transporters.MethodsSynovial tissues were taken from patients undergoing joint replacement surgery and fulfilling the 2010 ACR/EULAR RA criteria. Patients with no evidence of degenerative or inflammatory disease were used as control. Expression of the lactate transporters SLC16A1 and SLC16A3 on fibroblasts and macrophages was assessed by immunofluorescence staining and confocal microscopy. To test the effect of lactate in vitro we used RA synovial fibroblasts and monocyte-derived macrophages. Migration was assessed via scratch test assays or using trans-well inserts. Metabolic pathways were analysed by Seahorse analyser. IL-6 secretion was determined by ELISA. Bioinformatic analysis was performed on publicly available single cell and bulk RNA sequencing datasets.ResultsWe show that: i) SLC16A1 and SLC16A3 which regulate lactate intake and export respectively, are both expressed in RA synovial tissue and are upregulated upon inflammation. SLC16A3 is more highly expressed by macrophages, while SLC16A1 was expressed by both cell types. ii) This expression is maintained in distinct synovial compartments at mRNA and protein level. iii) Lactate, at the concentration found in RA joints (10 mM), has opposite effects on the effector functions of these two cell types. In fibroblasts, lactate promotes cell migration, IL-6 production and increases glycolysis. In contrast macrophages respond to increases in lactate by reducing glycolysis, migration, and IL-6 secretion.DiscussionIn this study, we provide the first evidence of distinct functions of fibroblasts and macrophages in presence of high lactate levels, opening new insights in understanding the pathogenesis of RA and offering novel potential therapeutic targets.

【 授权许可】

Unknown   
Copyright © 2023 Pucino, Nefla, Gauthier, Alsaleh, Clayton, Marshall, Filer, Clark, Raza and Buckley